Project Summary/Abstract The Usher Syndrome (USH) is a clinically and genetically heterogeneous disorder characterized by congenital deafness and retinitis pigmentosa. It is the most common cause of deafness accompanied by blindness. Hair cell replacement or regeneration therapies have not really solved the deafness problem of ear diseases. An alternative to replacing lost hair cells is to prevent their loss in the first place, which is a particularly promising line of investigation. Many USH patients will benefit from cochlear implants, but preservation of spiral ganglion cells is important for success of cochlear implants because a minimal density of spiral ganglion cells is required for effective cochlear implants. Residual hair cells present in the cochlea could promote the survival of spiral ganglion neurons by release of neurotrophic substances. Therefore, discovery of therapeutic targets that prevent hair cell death is the key to helping Usher 1 patients to respond to cochlear implants and other treatment options successfully. Mouse models facilitate experiments to determine the function of the various genes involved in Usher disease. We have developed mouse models for Usher syndrome. Thus, we propose the following specific aims: 1) identify the mutation in and characterize a new mouse deafness model (for Usher 1 syndrome and presbycusis) that provides an ideal window of time for evaluating drug therapy; 2) identify key molecules and mechanisms that lead to hair cell death and hearing loss in the models for the Usher 1 syndrome; 3) prove the concept that genetic hearing loss and hair cell death can be prevented by otoprotection therapy. Results of the proposed research will benefit human health.